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A new methodology is presented to synthesize in a regio and stereoselective manner tetrahydrofuro[3,2-b]furan-2(3H)-one, structural subunit present in a wide variety of natural products present in plant, fungi, algae, insects, and other living organisms. This secondary metabolites have important biological properties and have shown to be very active in different therapeutic areas. This method consists in the reaction of highly substituted 2-oxyallyl cations, generated in situ from the corresponding dihaloketone, and 2-functionalized furans (in our case 2-NHBoc-furan). It is a one-pot reaction that affords the desired furofuranones with high regio- and stereoselectivity. The new synthetic method is simple, straightforward and versatile, because a wide variety of furofuranones, and with wide molecular diversity, may be prepared by adequately designing the substituents of starting materials. The resulting furofuranones may be potentially derivatized to generate chemical libraries of high molecular diversity, which are very useful when developing structure–activity relationship studies.

(−)-(1R,2S,5R)-Menthyl (SS)-p-toluenesulfinate and its enantiomer are a common source for a chiral sulfoxide group in organic synthesis, by means of nucleophilic substitution. The replacement of the menthyloxy group, with complete inversion of configuration at the sulfur center of the chiral sulfoxide, allows the inclusion of this organic function into numerous substrates, with defined stereochemistry and high enantiomeric purity. Nine C3-substituted, enantiomerically pure, 2-sulfinylfurans were prepared by this synthetic methodology with moderate to high yields. These enantiopure C3-substituted 2-sulfinylfurans can be used as chiral dienes for [4+3] cycloaddition reactions and in other chemical transformations, in which π-facial selectivity should be induced in order to obtain enantioselective reactions.

The use of the p-tolylsulfinyl group as a chiral inductor in stereoselective [4+3] cycloaddition reactions has made possible the preparation of enantiopure polysubstituted 8-oxabicyclo[3.2.1]oct-6-en-3-one systems having up to five stereocenters. The presence in the furan diene of a susbtituent at the 3-position bearing an atom with lone-pair electrons propitiates the coordination of a metallic atom by the sulfoxide and the R3 “ligand” group. This chelation effect, together with the stereoelectronic demand of the R3 and sulfoxide groups, considerably decreases the degree of conformational freedom of the diene moiety in the cyclic transition state leading to the observed stereoselectivity. By choosing appropriate substituents in the furan ring, it is possible to obtain 100:0 cis-trans and 100:0 endo-exo diastereoselectivities. Up to 100 % π-facial diastereoselectivity (enantioselectivity after removal of the sulfoxide group) could be reached. Yields lie within the range of 50–80 %, depending on the furan substrate. However, if the furan diene is fitted with deactivating electron-withdrawing substituents, low conversions were observed under certain reaction conditions, but always with excellent-to-complete chemo- and stereoselectivities. The conversion and yield increase on introduction of an electron-donating substituent at the C-3 of the furan ring.

Several C-3 substituted furans with chelating groups have been reacted with 2,3-dibromo-3-pentanone in the presence of a reducing metal, resulting in the formation of [4+3]-cycloadducts with complete cis–trans and endo–exo diastereoselectivity and in excellent yield. A certain variability of the conversion and reaction yield could be observed, when changing the reaction conditions, but in all cases the stereoselectivity was complete, compared to that of C-3 substituted furans with non-chelating groups. Also, a general method of assignment of stereochemistry of cycloadducts has been established by NMR, considering diagnostic patterns of signals with different multiplicity and chemical shifts depending on the stereochemistry of diastereomeric cycloadducts.

Amido-1,3,4-thiadiazoles have been identified as a novel structural class of potent and selective sphingosine-1-phosphate receptor subtype 1 agonists. Starting from a micromolar HTS hit with the help of an in-house homology model, robust structural–activity relationships were developed to yield compounds with good selectivity and excellent in vivo efficacy in rat models.

Several 8-oxabicyclo[3.2.1]oct-6-en-3-ones are prepared by cycloaddition reaction of chiral furanes such as (I) and (VII) with dibromoketone (II).

A study of the induction of asymmetry on the [4+3] cycloaddition reaction of some 13 C2-substituted furan derivatives with 2-oxyallyl cation is presented. The asymmetry was induced by a chiral auxiliary on C2 of furan. A cis diastereospecificity and a high endo diastereoselectivity are observed in almost all studied cases. On decreasing the distance between the stereocenter of the chiral auxiliary and the reactive C2-carbon of the furan ring, the π-facial diastereoselectivity is increased, especially by using chiral furyl-sulfoxides.

A variety of C-3 functionalized chiral sulfoxide-containing furan derivatives is prepared, mainly based on manipulation of the carboxyl-moiety in (III).

A new methodology to perform [4+3] cycloaddition reactions of suitable dienes and 1,3-dimethyl-2-oxyallyl cations is presented. The reaction is carried out starting from commercially available dienes and easy-handling α,α′-diiodoketones, which are reduced by the Zn/Cu couple to generate the oxyallyl cation as intermediate. The reaction is carried out under mild thermal or sonochemical conditions at low temperatures (from 0 to −44°C) and for short reaction times (

The application of a new methodology to synthesize the C17–C23 subunit of Ionomycin is presented. This synthetic methodology is based on the preparation of heptane building blocks with four stereocenters and up to four different organic functionalities. 2,4-Dimethyl-1-methoxy-8-oxabicyclo[3.2.1]oct-6-en-3-one has been used as a key intermediate, which can easily be prepared by a [4+3] cycloaddition reaction between 2-methoxy-furan and the oxyallyl cation generated in situ from 2,4-dibromo-3-pentanone. This cycloadduct has an acetal functionality on C1 which allows the easy opening of the oxabicyclic system, affording versatile synthons.

A new synthetic methodology for preparing polyfunctionalized heptane building blocks with up to four stereocenters has been developed. 2,4-Dimethyl-1-methoxy-8-oxabicyclo-[3.2.1]-oct-6-en-3-one has been used as precursor, which can be easily prepared by a [4+3] cycloaddition reaction between 2-methoxy-furan and the oxyallyl cation generated in situ from 2,4-dibromo-3-pentanone. The cycloadducts have an acetal functionality on C1 which allows easy opening of the oxabicyclic system, affording versatile synthons. The application of this methodology to the synthesis of the C17–C23 subunit of Ionomycin is presented.

An study on the influence of steric and electronic effects of a function attached at C-2 of furans in the yield and diastereoselectivity of [4 + 3] cycloaddition reactions with oxyallyl cations is presented. In almost all studied furans a cis diastereospecificity and a high endo diastereoselectivity is observed. Increasing bulkyness of the function attached at C-2 of furans, the endo diastereoselectivity increases, but yield decreases. Increasing the electronic density of the furan system, by an electron donating group at C-2, both yield and diastereoselectivity increase.

Amido-1,3,4-thiadiazoles have been identified as a novel structural class of potent and selective sphingosine-1-phosphate receptor subtype 1 agonists. Starting from a micromolar HTS hit with the help of an in-house homology model, robust structural-activity relationships were developed to yield compounds with good selectivity and excellent in vivo efficacy in rat models.

A study on the influence of steric and electronic effects of a function attached at C-2 of furans in the yield and diastereoselectivity of [4+3] cycloaddition reactions with oxyallyl cations is presented. In almost all studied furans a cis diastereospecificity and a high endo diastereoselectivity is observed. Increasing bulkyness of the function attached at C-2 of furans, increases the endo diastereoselectivity, but decreases yield. Increasing the electronic density of the furan system, by an electron donating group attached at C-2, increases yield and diastereoselectivity.

An study on the influence of steric and electronic effects of a function attached at C-2 of furans in the yield and diastereoselectivity of [4 + 3] cycloaddition reactions with oxyallyl cations is presented. In almost all studied furans a cis diastereospecificity and a high endo diastereoselectivity is observed. Increasing bulkyness of the function attached at C-2 of furans, the endo diastereoselectivity increases, but yield decreases. Increasing the electronic density of the furan system, by an electron donating group at C-2, both yield and diastereoselectivity increase.

A new synthetic methodology for preparing polyfunctionalized heptane building blocks with up to four stereocenters has been developed. 2,4-Dimethyl-1-methoxy-8-oxabicyclo-[3.2.1]-oct-6-en-3-one has been used as precursor, which can be easily prepared by a [4+3] cycloaddition reaction between 2-methoxy-furan and the oxyallyl cation generated in situ from 2,4-dibromo-3-pentanone. The cycloadducts have an acetal functionality on C1 which allows easy opening of the oxabicyclic system, affording versatile synthons. The application of this methodology to the synthesis of the C17–C23 subunit of Ionomycin is presented.

A study of the induction of asymmetry on the [4+3] cycloaddition reaction of some 13 C2-substituted furan derivatives with 2-oxyallyl cation is presented. The asymmetry was induced by a chiral auxiliary on C2 of furan. A cis diastereospecificity and a high endo diastereoselectivity are observed in almost all studied cases. On decreasing the distance between the stereocenter of the chiral auxiliary and the reactive C2-carbon of the furan ring, the π-facial diastereoselectivity is increased, especially by using chiral furyl-sulfoxides.

An improved methodology to carry out [4C(4π;)+3C(2π;)] cycloaddition reactions of dienes and oxyallyl cations, is presented. The reaction starts from commercially available dienes and easy-handling α,α′-diiodoketones, which are reduced by Zn (powder) or Zn/Cu couple to generate an oxyallyl cation as an intermediate. The reaction is carried out under mild thermal or sonochemical conditions at low temperatures (from 0 to −44°C) and for short reaction times (

A study on the influence of steric and electronic effects of a function attached at C-2 of furans in the yield and diastereoselectivity of [4+3] cycloaddition reactions with oxyallyl cations is presented. In almost all studied furans a cis diastereospecificity and a high endo diastereoselectivity is observed. Increasing bulkyness of the function attached at C-2 of furans, increases the endo diastereoselectivity, but decreases yield. Increasing the electronic density of the furan system, by an electron donating group attached at C-2, increases yield and diastereoselectivity.

Ultrasound has been used as a source of energy in chemical reactions to increase both reaction rate and product yield. Ultrasonic horns can be used for this purpose on the laboratory scale. A homemade, safe, effective, and inexpensive reactor for ultrasonic horns with applications in microscale experiments in teaching and research laboratories is presented here. The vessel has two side necks for the insertion of either a flexible temperature probe, an inert-gas line adapter, or a septum to take samples from the reaction mixture. The reactor design allows work with small volumes (2-3 mL) optimal for microscale reactions. The tip of the sonication probe easily reaches the bottom of the vessel, producing vigorous agitation throughout the reaction medium. The design also facilitates temperature modulation with an external cooling bath, allowing reactions at low temperatures. This homemade reactor vessel for ultrasonic horns has only one-sixth the cost of the standard commercial reactors. The microscale sonica...